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ALAD

high resolution crystal structure of a mg2-dependent 5-aminolevulinic acid dehydratase

Identifiers

Symbol

ALAD

Pfam

PF00490

Pfam clan

CL0036

InterPro

IPR001731

PROSITE

PDOC00153

SCOP

1aw5

SUPERFAMILY

1aw5

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B₁₂, share porphobilinogen as a common precursor.

It catalyzes the second step of the biosynthesis of porphyrin. The porphobilinogen synthase catalyzed reaction is the first common step in the biosynthesis of all biological tetrapyrroles.

Porphobilinogen synthase is the prototype morpheein.^[1]

Structure[edit]

The structural basis for allosteric regulation of PBGS is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 6mer* ↔ 2mer* ↔ 2mer ↔ 8mer. The * represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers.^[1]

PBGS is encoded by a single gene and each PBGS multimer is composed of multiple copies of the same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzyme's active site in its center, and a >25 residue N-terminal arm domain. Allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain.

Each N-terminal arm has up to two interactions with other subunits in a PBGS multimer. One of these interactions helps to stabilize a "closed" conformation of the active site lid. The other interaction restricts solvent access from the other end of the αβ-barrel.

In the inactive mulimeric state, the N-terminal arm domain is not involved in the lid-stabilizing interaction, and in the crystal structure of the inactive assembly, the active site lid is disordered.

Allosteric Regulators of PBGS[edit]

As a nearly universal enzyme with a highly conserved active site, PBGS would not be a prime target for the development of antimicrobials and/or herbicides. To the contrary, allosteric sites can be much more phylogenetically variable than active sites, thus presenting more drug development opportunities.^[1]

Phylogenetic variation in PBGS allostery leads to the framing of discussion of PBGS allosteric regulation in terms of intrinsic and extrinsic factors.

Intrinsic allosteric regulators[edit]

Magnesium[edit]

The allosteric magnesium ion lies at the highly hydrated interface of two pro-octamer dimers. It appears to be easily dissociable, and it has been shown that hexamers accumulate when magnesium is removed in vitro.^[2]

pH[edit]

Though it is not common to consider hydronium ions as allosteric regulators, in the case of PBGS, side chain protonation at locations other than the active site has been shown to affect the quaternary structure equilibrium, and thus to affect the rate of its catalyzed reaction as well.

Extrinsic allosteric regulators[edit]

Small molecule hexamer stabilization[edit]

Inspection of the PBGS 6mer* reveals a surface cavity that is not present in the 8mer. Small molecule binding to this phylogenetically variable cavity has been proposed to stabilize 6mer* of the targeted PBGS and consequently inhibit activity.

Such allosteric regulators are known as morphlocks because they lock PBGS in a specific morpheein form (6mer*).^[3]

Deficiency[edit]

A deficiency of porphobilinogen synthase is usually acquired (rather than hereditary) and can be caused by heavy metal poisoning, especially lead poisoning, as the enzyme is very susceptible to inhibition by heavy metals.^[4]

Hereditary insufficiency of porphobilinogen synthase is called porphobilinogen synthase (or ALA dehydratase) deficiency poprhyria. It is an extremely rare cause of porphyria,^[5] with less than 10 cases ever reported.^[6] All disease associated protein variants favor hexamer formation relative to the wild type human enzyme.^[5]

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

Lead poisoning works on the cellular level by binding to this enzyme, rendering it useless.

PBGS as the prototype morpheein[edit]

The morpheein model of allostery exemplified by PBGS adds an additional layer of understanding to potential mechanisms for regulation of protein function and complements the increased focus that the protein science community is placing on protein structure dynamics.^[1]

This model illustrates how the dynamics of phenomena such as alternate protein conformations, alternate oligomeric states, and transient protein-protein interactions can be harnessed for allosteric regulation of catalytic activity.

References[edit]

^ ^a ^b ^c ^d Jaffe EK, Lawrence SH (March 2012). "Allostery and the dynamic oligomerization of porphobilinogen synthase". Arch. Biochem. Biophys. 519 (2): 144–53. doi:10.1016/j.abb.2011.10.010. PMC 3291741. PMID 22037356.
^ Breinig S, Kervinen J, Stith L, Wasson AS, Fairman R, Wlodawer A, Zdanov A, Jaffe EK (September 2003). "Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase". Nat. Struct. Biol. 10 (9): 757–63. doi:10.1038/nsb963. PMID 12897770.
^ Lawrence SH, Jaffe EK (2008). "Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching using Morpheeins". Biochem Mol Biol Educ 36 (4): 274–283. doi:10.1002/bmb.20211. PMC 2575429. PMID 19578473.
^ ALA dehydratase reaction, from NetBiochem at the University of Utah. Last modified 1/5/95
^ ^a ^b Jaffe EK, Stith L (February 2007). "ALAD porphyria is a conformational disease". Am. J. Hum. Genet. 80 (2): 329–37. doi:10.1086/511444. PMC 1785348. PMID 17236137.
^ Overview of the Porphyrias at The Porphyrias Consortium (a part of NIH Rare Diseases Clinical Research Network (RDCRN)) Retrieved June 2011

External links[edit]

delta-Aminolevulinic Acid Dehydratase at the US National Library of Medicine Medical Subject Headings (MeSH)
http://www.omim.org/entry/125270?search=pbgs&highlight=pbgs

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. ALA脱水酵素欠損性ポルフィリン症 ala dehydratase porphyria
2. チロシン代謝障害 disorders of tyrosine metabolism
3. 全身疾患と関連した遺伝性ニューロパチー hereditary neuropathies associated with generalized disorders
4. ポルフィリン症：概要 porphyrias an overview
5. 急性間欠性ポルフィリン症の病因、臨床症状および診断 pathogenesis clinical manifestations and diagnosis of acute intermittent porphyria

English Journal

The relationship between selected VDR, HFE and ALAD gene polymorphisms and several basic toxicological parameters among persons occupationally exposed to lead.

Szymańska-Chabowska A1, Łaczmański Ł2, Jędrychowska I1, Chabowski M3, Gać P4, Janus A1, Gosławska K1, Smyk B1, Solska U1, Mazur G1, Poręba R5.
Toxicology.Toxicology.2015 Aug 6;334:12-21. doi: 10.1016/j.tox.2015.05.002. Epub 2015 May 8.
The aim of this study was to find a relationship between polymorphisms of ALAD rs1805313, rs222808, rs1139488, VDR FokI and HFE C282Y and H63D and basic toxicological parameters (lead and ZnPP blood concentration) in people occupationally exposed to lead. We collected data of 101 workers (age 25-63
PMID 25963508

A novel mutation, IVS2-2AgG, associated with acute intermittent porphyria in a Chinese family.

Jiao H1, Xianfeng Z1, Hui H1; MaLizhen, Yuhong Z1, Chu Z1.
JPMA. The Journal of the Pakistan Medical Association.J Pak Med Assoc.2015 Aug;65(8):898-900.
Porphyria is a group of disorders caused by the accumulation of porphyrin and porphyrin precursors due to the abnormalities in certain enzymes that normally participate in the production of haem. We report a case of a woman with severe menstruation-related abdominal pain, hyponatraemia, and psychiat
PMID 26228342

High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria.

Pallet N1, Mami I2, Schmitt C3, Karim Z4, François A5, Rabant M6, Nochy D7, Gouya L3, Deybach JC3, Xu-Dubois Y8, Thervet E9, Puy H3, Karras A9.
Kidney international.Kidney Int.2015 Aug;88(2):386-95. doi: 10.1038/ki.2015.97. Epub 2015 Apr 1.
Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and
PMID 25830761

Japanese Journal

False-Positive Accumulation of Metaiodobenzylguanidine in a Case with Acute Intermittent Porphyria

Masuda Tomoko,Ota Rie,Ando Takao,Maeda Naoto,Horie Yutaka,Yoshimura Toshiro,Motomura Masakatsu,Kawakami Atsushi
Internal Medicine 50(9), 1029-1032, 2011
… A diagnosis of acute intermittent porphyria was finally confirmed based on the characteristic pictures, increased urinary excretion of porphobilinogen, and identification of a heterozygous missense mutation of R173W in the hydroxymethylbilane synthase gene. …
NAID 130000650107

Effect of Culture Conditions on Production of 5-Aminolevulinic Acid by Recombinant Escherichia coli

Lee Dae-Hee,Jun Woo-Jin,Shin Dong-Hoon [他],CHO Hong-Yon,HONG Bum-Shik
Bioscience, biotechnology, and biochemistry 69(3), 470-476, 2005-03-23
… Aminolevulinic acid (ALA) is formed by the enzyme ALA synthase (<I>hemA</I> … Then ALA is converted to Porphobilinogen (PBG) by the ALA dehydratase (<I>hemB</I> … The effects of pH on the ALA synthase and ALA dehydratase were investigated. … The ALA synthase and ALA dehydratase activities were dependent on the pH of the medium, with maximal activities occurring at pH 6.5 and 8.0 respectively. …
NAID 130000030383

Purification and Characterization of the Clostridium josui Porphobilinogen Deaminase Encoded by the hemC Gene from a Recombinant Escherichia coil

Fujino Emi,Fujino Tsuchiyoshi,Karita Shuichi [他],KIMURA TETSUYA,SAKKA KAZUO,OHMIYA KUNIO
Journal of bioscience and bioengineering 87(4), 535-537, 1999-04-25
… The porphobilinogen deaminase encoded by the Clostridium josui hemC gene was purified from a recombinant Escherichia coli strain and its properties were characterized. … The K_m and V_max values of the enzyme were 65μM and 3.3μmol/h/mg for porphobilinogen, respectively. …
NAID 110002684306

Related Pictures

★リンクテーブル★

リンク元	「アミノレブリン酸脱水酵素」
関連記事	「synthase」「porphobilinogen」

「アミノレブリン酸脱水酵素」

Delta-aminolevulinic acid dehydratase
Identifiers
Symbol	ALAD
Entrez	210
HUGO	395
OMIM	125270
RefSeq	NM_001003945
UniProt	P13716
Other data
Locus	Chr. 9 q32

Search
PMC	articles
PubMed	articles
NCBI	proteins

porphobilinogen synthase
Identifiers
EC number	4.2.1.24
CAS number	9036-37-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search
PMC	articles
PubMed	articles
NCBI	proteins

　　[★]

英: aminolevulinic acid dehydratase
同: アミノレブリン酸脱水酵素、δ-アミノレブリン酸脱水酵素、ポルフォビリノゲンシンターゼ porphobilinogen synthase
関: ポルホビリノーゲン、ヘム、ポルフィリン

[show details]

ポルフォビリノーゲンシンターゼ : 86 件
ポルホビリノーゲンシンターゼ : 32 件
ポルフォビリノゲンシンターゼ : 86 件
ポルホビリノゲンシンターゼ : 8 件
ポルフォビリノーゲン合成酵素 : 40 件
ポルホビリノーゲン合成酵素 : 15 件
ポルフォビリノゲン合成酵素 : 40 件
ポルホビリノゲン合成酵素 : nothing

アミノレブリン酸脱水酵素 : 約 11,200 件
アミノレブリン酸デヒドラターゼ : 約 10,200 件

概念

細胞質に存在
Znを含む酵素　　←　　鉛中毒と関係あるんだっけ？
2分子の5-アミノレブリン酸からポルホビリノゲンシンターゼにより1分子のポルホビリノゲンを生成する
鉛によって阻害され、鉛中毒を呈する。

「synthase」

　　[★]

n.

(脱離酵素リアーゼの逆反応である合成方向の反応を指す) シンターゼ, 合成酵素, 付加酵素

関: lyase、synthetase、transferase

「porphobilinogen」

　　[★] ポルホビリノーゲン PBG

[Jaffe_Lawrence_2012-1] Jaffe EK, Lawrence SH (March 2012). "Allostery and the dynamic oligomerization of porphobilinogen synthase". Arch. Biochem. Biophys. 519 (2): 144–53. doi:10.1016/j.abb.2011.10.010. PMC 3291741. PMID 22037356.

[Breinig_2003-2] Breinig S, Kervinen J, Stith L, Wasson AS, Fairman R, Wlodawer A, Zdanov A, Jaffe EK (September 2003). "Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase". Nat. Struct. Biol. 10 (9): 757–63. doi:10.1038/nsb963. PMID 12897770.

[pmid19578473-3] Lawrence SH, Jaffe EK (2008). "Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching using Morpheeins". Biochem Mol Biol Educ 36 (4): 274–283. doi:10.1002/bmb.20211. PMC 2575429. PMID 19578473.

[4] ALA dehydratase reaction, from NetBiochem at the University of Utah. Last modified 1/5/95

[Jaffe_Stith_2007-5] Jaffe EK, Stith L (February 2007). "ALAD porphyria is a conformational disease". Am. J. Hum. Genet. 80 (2): 329–37. doi:10.1086/511444. PMC 1785348. PMID 17236137.

[6] Overview of the Porphyrias at The Porphyrias Consortium (a part of NIH Rare Diseases Clinical Research Network (RDCRN)) Retrieved June 2011

匿名

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案内

案内

porphobilinogen synthase